Abstract Fragile X syndrome (FXS) is associated with an increased risk of autism spectrum disorder (ASD), with prevalence rates ranging from ~40-74%1-6, suggesting that the FMR1 gene (the gene causing FXS) and its protein product, the Fragile X Mental Retardation Protein (FMRP), constitute a highly important risk for ASD symptomatology. Importantly, ASD-related features (i.e., the broad autism phenotype, or BAP) have also been observed at elevated rates among carriers of the FMR1 premutation (PM carriers), providing further evidence of the role of FMR1-related variation in ASD-related phenotypes. In the original period of funding, this project identified a number of clinical, psycholinguistic, and social-cognitive features that may serve as candidate endophenotypes (i.e., heritable traits associated with a disease and measurable in affected and unaffected individuals) overlapping in ASD and FXS, which were also evident among first-degree relatives at increased genetic liability (and in the case of FXS, PM carriers). In this revised renewal application, we build on these promising findings with deep behavioral and neural phenotyping in the domain of pragmatic language (where we have demonstrated robust overlap in profiles in ASD and FMR1 mutations (PM carriers and FXS). In particular, we apply multi-method assessments of prosody (e.g., intonation, stress, and rhythm of language), which is a critical pragmatic skill that is impaired in ASD (and linked with social impairments), and also impacted in the BAP in unaffected relatives. Analyses include data from three independent cohorts with extensive existing data available for computational and data-driven analyses to identify phenotypically-defined homogeneous subgroups that may cross diagnostic borders and provide clues to biological mechanisms that can inform studies of etiology and treatment. Preliminary data suggest that these pragmatic and prosodic profiles are associated with the neural processing of speech sounds, with robust differences in the neural frequency following response (FFR). The FFR is a precise neural index of spectral and temporal encoding of sound within the midbrain, that serves as a barometer of rapid auditory processing that is linked to expressive and receptive speech and language-related skills throughout the lifespan7-13. FMRP is highly expressed in the auditory midbrain, making our focus on the spectral and temporal encoding of speech within the midbrain a particularly strong candidate as a neural marker linked with FMR1, and relevant to the pathogenesis of language-related features in ASD. In this renewal application, we investigate the FFR together with a multi- context assessment of prosody in PM carriers (leveraging data from three independent cohorts and applying sophisticated computational modeling of prosody across different conversational contexts) to detect key ASD- related pragmatic and neural phenotypes linked with FMR1-related variation that have significant potential to illuminate the pathogenesis of ASD and inform treatment.